A role for peroxiredoxins in H2O2- and MEKK-dependent activation of the p38 signaling pathway

Ana G. Barata, Tobias P. Dick

Research output: Contribution to journalArticle

Abstract

The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in the cellular response to various stresses and its deregulation accompanies pathological conditions such as cancer and chronic inflammation. Hydrogen peroxide (H2O2) is a well-established activator of the p38 MAPK signaling pathway. However, the mechanisms of H2O2-induced p38 activation are not yet fully understood. In Drosophila cells, we find that H2O2-induced activation of p38 depends on the MAPK kinase kinase (MAP3K) Mekk1. In line with the emerging role of peroxiredoxins as H2O2 sensors and signal transmitters we observe an H2O2-dependent interaction between Mekk1 and the cytosolic peroxiredoxin of Drosophila, Jafrac1. In human cells, MEKK4 (the homologue of Mekk1) and peroxiredoxin-2 (Prx2) interact in a similar manner, suggesting an evolutionarily conserved mechanism. In both organisms, H2O2 induces transient disulfide-linked conjugates between the MAP3K and a typical 2-Cys peroxiredoxin. We propose that these conjugates represent the relaying of oxidative equivalents from H2O2 to the MAP3K and that the oxidation of Mekk1/MEKK4 leads to the downstream activation of p38 MAPK. Indeed, the depletion of cytosolic 2-Cys peroxiredoxins in human cells diminished H2O2-induced activation of p38 MAPK.

Original languageEnglish (US)
Article number101340
JournalRedox Biology
Volume28
DOIs
StatePublished - Jan 2020

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Peroxiredoxins
MAP Kinase Kinase Kinases
Mitogen-Activated Protein Kinases
Hydrogen Peroxide
p38 Mitogen-Activated Protein Kinases
Chemical activation
Drosophila
Cells
Deregulation
Disulfides
Transmitters
Inflammation
Oxidation
Sensors
Neoplasms

Keywords

  • HO signaling
  • Hydrogen peroxide
  • MEKK4
  • Mitogen activated protein kinase
  • p38
  • Peroxiredoxins
  • Redox relays

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

Cite this

A role for peroxiredoxins in H2O2- and MEKK-dependent activation of the p38 signaling pathway. / Barata, Ana G.; Dick, Tobias P.

In: Redox Biology, Vol. 28, 101340, 01.2020.

Research output: Contribution to journalArticle

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